The World's Most Important AIDS Research?
Despite the effectiveness of anti-HIV therapy and considerable success in reducing the price of the drugs in resource-poor settings, the relentless spread of HIV continues to overwhelm all efforts to contain it. AIDS cannot be stopped without an effective means of preventing future infections. Unfortunately, the quest for a vaccine continues to elude our best scientific efforts. The new vaccines that looked so promising a few short years ago have produced disappointing results in early human studies. What happened in the animal models does not seem to happen in humans.
Some scientists argue that there is no guarantee we will ever have a vaccine, while others are more optimistic but recognize that HIV presents a uniquely difficult challenge. Yet even if a perfect vaccine were created today, it would take roughly ten years to prove its effectiveness. It is difficult to overstate the damage that another ten years without a vaccine will do.
Given the high stakes, some researchers and public health specialists are increasingly asking whether there might be other ways of preventing the spread of HIV. Certainly, everyone recognizes the role of behavioral prevention campaigns, but these approaches are today often bogged down by political and religious debate. Condom distribution and needle exchange must be considered the first-line defense, as these are best supported by scientific evidence. Over the last four years, however, other voices have come into positions of power, insisting that sexual abstinence must instead be emphasized, particularly among the young. They argue, unsupported by evidence, that condoms and needle exchange encourage risky behavior and that only abstinence can prevent or reduce HIV transmission. While no one opposes the concept of sexual abstinence among the young, it is a misrepresentation of the evidence to suggest that abstinence campaigns have been shown to be an effective alternative to condom and needle distribution. While the debate continues, pitting the scientifically proven tools of prevention against religious and politically inspired beliefs, the band plays on -- as was so aptly said back in 1987.
AIDS is a disease whose spread is facilitated by human behavior. Thus, stopping it is almost certain to require behavioral change. A growing majority of new infections occur among women, particularly women who have minimal control over the factors that result in HIV transmission. For these women, there is often little or no choice involved, no opportunity to choose either condoms or abstinence. Even where condoms are universally available, they are only effective when both parties agree to their use. Condom distribution, needle exchange and abstinence education all have a role to play in combating HIV, but for an increasing majority of people at risk of HIV infection, they are not sufficient.
Prevention tools are needed that are under the control of the individual, require little or no support from sexual partners and are largely invisible to other parties, just as a vaccine is. Surprisingly, there are at least two types of tools that could be made readily available in the near future, long before any possible vaccine, and which are far more practical in the long-term than relying on behavior change alone to contain the spread of HIV. One is topical prevention with HIV microbicides. These are substances which either destroy or block the replication of HIV and which can be applied to the body at the various possible points where contact might occur between bodily fluids. Making an effective microbicide will require selection of the most effective products as well as their testing in humans. The other type of tool involves the use of certain oral anti-HIV medications taken either before a potential HIV exposure or on a steady state basis. This approach is sometimes called pre-exposure prevention or PREP. It relies on certain types of already available anti-HIV medication and requires only an accelerated testing in volunteers. Developing these two technologies may well be the world's most important AIDS research and may offer the only realistic hope of slowing the spread of HIV over the next decade or longer.
Option One: Microbicides
A microbicide is a chemical that directly or indirectly destroys a microbe (in this case, HIV). An effective microbicide would give people an HIV prevention tool that is more in their own control. Such a product would likely be a gel, liquid, suppository or perhaps a lubricant, which could be self-applied prior to sexual activity. It might be able to be used vaginally or rectally, or both. The concept is neither untried nor unproven. Spermicides have been used to prevent pregnancy for decades. The case for accelerated development of HIV microbicides has been endorsed by UNAIDS, the World Health Organization, the International Program for Microbicides, the Population Council and other international agencies.
The importance of microbicide development is hard to overstate, whether looking at national or international expressions of the HIV pandemic. In sub-Saharan Africa, women account for more than 50% of the HIV infections. Among teens in some African countries, the ratio of HIV-infected girls to boys is nearly 6 to 1. These figures reflect the fact that teenage girls are commonly forced into sex and in a male-dominated culture with low use of condoms. A prevention method that can be both woman-initiated and woman-controlled is desperately needed. Though the ratios might be different in developed nations, women even in the U.S. sometimes find themselves in similar situations and have a similar need for a prevention method which they can control. Microbicides aren't a perfect answer for women in relationships where there is violence and sexual power imbalances, but they do offer an improvement over current options. When combined with other prevention strategies, they may be enough to significantly turn the tide of the epidemic.
Microbicides may also become an important prevention tool for men. HIV infection rates are on the rise again in many cities with large gay communities. Most observers believe this reflects an increased level of unprotected sexual activity, particularly anal intercourse without condoms. Whatever the rationale for disregarding condom use, it is clear that an effective microbicide/lubricant could play a critical role in slowing the renewed spread of HIV.
Given the obvious need, why isn't microbicide development a front burner issue for AIDS research and AIDS activism? With the exception of the Global Campaign for Microbicides (www.global-campaign.org), few community groups specialize in this area. The effectiveness of condom programs in the developed nations perhaps led to a lack of emphasis on the need for prevention alternatives. But times have changed and the use of condoms seems to have declined. Some speculate that this is simply part of the tendency among younger gay men to feel less threatened by AIDS. Condom use has never been high in resource-poor settings, but the needs of such settings have never had much influence on what technologies industry invests in. Resource-poor nations have always presented a dilemma for industry. Companies tend to see them as places where their products, though desperately needed, can't be sold at a sufficient profit to attract much interest in the board room. Perhaps the biggest question then is why government, both the U.S. government and others around the world, have not more heavily invested in microbicide development. For years, government funding has been driven by the assumption that a vaccine was never far off, a view that now seems laughably inaccurate. Yet this view almost certainly contributed to the lack of funding for vaccine alternatives.
Microbicide research can take multiple forms. Some companies are seeking to develop new compounds that can destroy or disable HIV on contact, without damaging surrounding tissue. Another approach, currently at the proposal stage, is to make use of the new class of anti-HIV drugs called "AFE" inhibitors ("Attachment, Fusion, and Entry" inhibitors). With one very expensive exception though, these are drugs that are at least two years away from approval by the FDA. Still, they could be tested as microbicides at the same time they are being developed as drugs to treat HIV. This could result in their approval as microbicides long before any vaccine makes it to the approval stage. As a general rule, it should take less time to put a microbicide through the development and approval process than a vaccine. If the products were proven safe early on, they could be put into use well in advance of formal approval based on preliminary data.
The one known technical obstacle which has slowed microbicide development is the lack of a suitable placebo to serve as a control in clinical studies. To be useful, a placebo must be visibly and sensually indistinguishable from the real microbicide, and it must not produce any changes of its own in the mucosal area where it will be applied. So far, no one has been able to create a placebo that meets this requirement, and without one, the only way to get a reliable answer from a study is to include a much larger number of volunteers and follow them for a much longer time. This would make the study far more expensive. Still, it would be a mistake to say that this problem explains why microbicide development hasn't been faster. It is primarily a matter of will and a matter of money. Those who truly care about the frightening spread of the disease in Africa, Asia, Eastern Europe and South and Central America, as well as the renewed rise of HIV infection rates in the U.S., need to raise their voices and demand a higher priority for such research.
Option Two: Pre-Exposure Treatment as Prevention
The second alternative that might be employed while waiting for a vaccine is the use of certain readily available, approved anti-HIV drugs in HIV-negative people. This idea first came to prominence several years ago during the early development of the anti-HIV drug tenofovir (Viread). In 1995, before it was widely tested in humans, scientists reported on the results of an experiment in which monkeys were given a single dose of tenofovir and then deliberately exposed to SIV, a close relative of HIV which infects many primates. A similar group of monkeys was also injected with SIV but not given tenofovir. The results were striking: all the animals that received tenofovir remained uninfected by the SIV challenge. They appeared to be protected for at least several days from a single injection, while all the animals who received the same SIV challenge without first receiving tenofovir were readily infected with SIV. The result appeared to be related both to the drug's mechanism of action and the fact that it remained in the blood for a long period after a single dose.
Today, tenofovir is approved for the treatment of HIV. It has quickly become popular due to its once-a-day dosing. It's stable in the body for long periods and it seems to be relatively powerful and generally free of major side effects. It is thus an attractive candidate for testing as a preventive tool.
Researchers are now attempting to conduct studies using tenofovir as a preventive. Given the pressing need for user-controlled HIV prevention tools and the lack of a vaccine that could be ready soon, these studies should rank among the highest priorities of AIDS researchers, public health experts, and activists alike. But such is not the case and several obstacles have slowed the progress of these studies. The sense of urgency that once drove every aspect of AIDS activism seems now seems to be outweighed by other concerns.
One study, with female sex workers in Cambodia, became the subject of protest from activists at the International AIDS Conference in Bangkok this summer. Some advocates argued that the study must guarantee free medical care for any possible drug side effects for 30 years after the start of the study and must provide a free anti-HIV drugs for a lifetime for anyone who becomes infected during the study. While a drug company should certainly take responsibility for damage done by side effects in a study, it is unprecedented to expect a company to provide guaranteed care for possible side effects for 30 years. Any time beyond the first few years after a study ends, it becomes very difficult to determine whether medical events are or are not related to a drug a person took in the past. A guarantee of 30 years support is an open-ended financial commitment that few (if any) companies would ever undertake.
It is an especially difficult thing to ask of a company that wasn't sponsoring the study in the first place (U.S. government agencies were sponsoring the study). It is just as difficult to ask a government to make such a commitment, even with a drug that is so far known to be particularly safe compared to other HIV medications. Similarly, while lifetime treatment for HIV is a benefit that should be due to anyone who is HIV infected, such a request in association with a research study becomes very problematic in a country where guarantees of treatment are not otherwise provided. Some would see offering such a benefit as a form of coercion to get people to participate in the study.
Both demands are no doubt attempts to meet the real needs of people in a resource-poor setting. Nonetheless, there is only so much of the burden of healthcare that can be carried by a single study. These demands have brought the Cambodian study to a halt and since the grant which funds the study expires this year, there seems little chance it can be brought back to life. At the very least, it will require renewal of the grant, which is no simple matter. Additionally, the controversy and anger that have been stirred up have left the Cambodian population and its government angry and divided. While some people believed the study would exploit poor Cambodian women, public health experts and researchers argued that by far the greatest threat to Cambodian sex workers is the unchecked spread of HIV. From their point of view, the study offered the first real hope of breaking the cycle of HIV infection.
The simplest solution is to conclude that if these are the terms demanded by the potential study subjects, their government or their advocates in Cambodia, then perhaps the study should not be run there. The critical scientific questions can be answered by the five other studies of this approach underway in other countries. Still, it will be sad to see two years of work and planning, as well as the contributions of Cambodian study volunteers, come to naught. Researchers need to carefully examine what happened in Cambodia and how it might be avoided in the future. It is unlikely that any research studies are going to provide lifetime treatment guarantees or 30 years of financial responsibility for possible side effects. But it may be possible to find other ways to meet those needs before asking the poorest of people to volunteer for studies in the future.
The five other studies which should soon be underway include one in Atlanta and another in San Francisco, both seeking sexually active volunteers from the gay community. These studies have also been under development and discussion for nearly two years and neither study has yet put its first volunteers on treatment (though this may change by publication date). If there is a positive finding in such studies, it holds the promise of changing the direction of the epidemic. Word of the study alone has already led to many people, sometimes with the support of their doctors, to make tenofovir a part of their "weekend" cocktails out on the party circuit. Though this is clearly premature, who can blame them? It would be far better though, if we could provide people with reliable, proven information, and for that, the studies must move forward.
While tenofovir may make the most sense for this application today, this could well change when the the new class of entry inhibitor drugs reaches approval. For the same reason such drugs are attractive as the building blocks of microbicides, so too are they attractive as potential oral infection-blockers. The combination of a mechanism of action that targets early steps in the virus' life cycle, low toxicity, and slow clearance from the blood contribute to make a drug a good candidate for treatment-as-prevention.
Most public health experts would prefer to address the problem of HIV transmission with the tried and true approach of a vaccine. At 20 plus years into the AIDS pandemic though, it is no longer enough to hope and wait for such a vaccine. There are alternatives, some of them behavioral and some of them chemical. We must exploit every possible means to slow the spread of HIV.
In debates over behavioral approaches, there are too many lives at stake to simply argue about condoms vs. abstinence. There is room, and need, for both, and there are people of goodwill on all sides of the debate. They go wrong only when they promote their own preferred approach to the exclusion of all others.
When it comes to microbicides and the use of treatment-as-prevention, we need only apply the same rules and values we adhered to in the development of therapy. It is too soon to forget how desperately the first therapies were needed and how important it was to confront obstacles that slowed their study. For the sake of millions more who will be infected five years from now or ten years from, we must be equally intolerant of delays and obstacles to the development of microbicides and treatment-as-prevention. No one will support studies that breach our understanding of ethics and protection of human subjects, but we must never forget that people pay with their lives for each day of delay that we cause or tolerate.
There are genuinely promising solutions to the dilemmas of prevention within our grasp. They can be achieved far more easily than a vaccine, and they can buy us much needed time to develop a vaccine, however long it may take. Nothing would be worse than to look back ten years from now and see that we squandered the potential opportunities offered by microbicides and treatment-as-prevention.
Antiretroviral Drug Researchers, AIDS Advocates Fail to Reach Consensus Over Viread Trials in Developing Countries
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